The goal of the proposed studies is to evaluate the role of neuronal insulin signaling in the expression of ethanol-related behaviors in mice. Converging evidence suggests that insulin might mediate the perception of reward from food, ethanol, and drugs of abuse by acting directly in the brain. The proposed research will use the new technology of small hairpin RNAs to selectively down regulate the expression of the insulin receptor in two brain regions implicated in ethanol abuse and dependence: the ventral tegmental area and nucleus accumbens. The effect of knocking down insulin receptor on ethanol-related behaviors will be examined using ethanol conditioned place preference, a standard model of drug reward. The role of insulin degrading enzyme, which is responsible for the primary step in insulin degradation, will also be studied in ethanol conditioned preference as well as in ethanol intake. These latter experiments will utilize transgenic mice that show approximately two-fold overexpression of insulin degrading enzyme only in the nervous system. One mechanism of insulin's effects on reward related behaviors has been proposed to be through modulation of dopaminergic signaling, and in particular, through regulation of dopamine transporter expression and function. Regulation of the dopamine transporter by insulin signaling will therefore be examined in the small haripin RNA injected mice and in the transgenic over expressing mice. Relevance: Insulin provides basic information to the brain regarding energy state, and regulates feeding and other motivated behaviors through direct actions in discrete brain nuclei. Since alcohol abuse and dependence are clearly motivated behaviors, an understanding of the role of insulin signaling in models of these diseases like will lead to a better understanding of the neurobiological processes that underlie ethanol-related behaviors, and may lead to the development of therapeutic interventions to reduce alcoholism.